Colorectal carcinoma is a malignant tumor of the colon, in Europe belonging to the most widespread types of tumor diseases. Annually, almost 7 500 new cases of this disease are diagnosed and each year more than 4 000 of patients die of this disease. Over 50% of these tumors are localized in the rectum and 20% of them attack sigmoideum. Only about 15% of tumors were found in the colon proper, of them about 6 to 8% in the colon transversum and about 6 to 7% in the colon descendens. Despite differences in their anatomic location, the mentioned tumors are regarded as affection of one organ and are denoted as the colorectal carcinoma. Women suffer from colorectal carcinoma more often in the region of colon whereas men are more often affected in the rectal region. Clinical symptoms of colorectal carcinoma are manifested by its localization, magnitude of the mechanical obstruction and the overall response of the organism. The enterostenosis manifests itself by meteorism, change in defecation habits, colical pain, and in some cases by sudden ileus. An exulceration of the tumor manifests itself by microscopic or macroscopic bleeding and subsequent anemia.
Treatment of many tumor diseases makes use of platinum complexes. So far, the therapeutic practice uses only complexes of bivalent platinum, such as cisplatinum, carboplatinum and oxaliplatinum. However, these bivalent platinum complexes are unstable in the gastrointestinal tract and/or they are poorly absorbable by the organism. These properties of bivalent platinum complexes make their use in an oral dosage form impossible. Recently, it has been found that some of the new prepared complexes of tetravalent platinum retain their antitumor activity even when administered orally. Such complexes have been described in patent documents EP 0 328 274, EP 0 423 707 and PCT/CZ99/00015 as new substances for oral application.
Another possible application of platinum complexes is the rectal administration in which the platinum complex avoids the aggressive medium of the gastrointestinal tract and after absorption by the rectal mucosa it passes via the portal system directly into the systemic blood circulation. The possibility of rectal application of a tetravalent platinum complex has been described in U.S. Pat. No. 6,033,683.
In comparison with other application methods, oral administration of platinum complexes represents the most comfortable way for the patient and therefore oral application of a solid dosage form of a platinum complex, enabling release of the platinum complex only in the region of colon appears as very prospective and promising. Such oral colonic application of drugs has its history in application of antirheumatics or in protection of mucous membranes of the gastrointestinal tract by administration of peptides and proteins. In the mentioned cases, drugs or protective substances are applied orally in the form of their conjugates with auxiliary substances, particularly in the form of azo conjugates, cyclodextrin conjugates, glycoside conjugates, glucuronate conjugates, dextran conjugates, polypeptide conjugates and conjugates with polymers, or in a form protected by degradable polymer coating, particularly by a pH-sensitive or biodegradable polymer coating, or in a form sealed in capsules of a biodegradable polymer, preferably sealed in hard capsules, or in the form of a system of anchored drug or protective substance, preferably in the form of a biodegradable polymer and hydrogel matrices, or in the form of a pH-sensitive polymer matrices. All these systems protect the orally applied drug or protective substance from the aggressive medium of the gastrointestinal tract before it enters the large intestine.
Complexes of tetravalent platinum in general exhibit very poor solubility in water, low bulk density, low tap density, and a very high electrostatic charge. These properties represent a significant problem in the preparation of an oral solid dosage form. Moreover, complexes of tetravalent platinum are chemically unstable in contact with metals or with many currently used pharmaceutical excipients, which poses a great problem for keeping stability of the active substance in the oral solid dosage form. These problems have been partially solved by an oral dosage form of a tetravalent platinum complex, described in PCT/CZ99/00015 which provides preparation of an oral solid dosage form containing a complex of tetravalent platinum in the form of its soluble inclusion complexes with cyclodextrins, and subsequent lyophilization. However, this method of preparation is complicated and expensive, and the limited capacity of cyclodextrin significantly limits the content of the tetravalent platinum complex present in the cyclodextrin inclusion complex. The possibility of manufacturing a stable oral dosage form containing a complex of tetravalent platinum has been disclosed in patent application CZ 2004-235 which specifies excipients compatible with tetravalent platinum complexes.
The possibility of enterosolvent application of platinum complexes, i.e. their targeted application in the region of small intestine and their possible controlled release in this region, in an oral application has been described in PCT/CZ2004/000017. However, the possibility of oral application of a solid dosage form of platinum complexes, that would allow their colonic release, has not been hitherto described.
Therefore, this invention discloses an oral pharmaceutical composition for a targeted transport of a platinum complex into the colorectal region.